Ulcerative colitis (UC) is a debilitating disease that affects ~700,000 people in the US alone. Although enema products for UC are more efficacious and have fewer side effects than oral therapy, drug enema products typically provide <40% remission after 6-8 weeks of daily treatment, leaving substantial room for improvement in enema design for UC. Since drugs for UC can only exert their therapeutic effect when delivered topically to the affected colorectal tissue, it is vital to deliver high concentrations of drug uniformly throughout the colorectal epithelium. However, we found that colorectal mucus is a significant barrier to colorectal distribution of conventional drug delivery systems, including the micronized drug particles in conventional enema products and conventional mucoadhesive nanoparticle systems. Micronized drug particles that are too large to pass through the mucus mesh, and adhesive particles that stick to mucus, do not provide uniform drug delivery to the underlying colorectal epithelium, and are rapidly cleared via normal mucus clearance mechanisms. In contrast, we have developed non-adhesive mucus-penetrating particles (MPP), and our pilot data suggests they rapidly penetrate through colorectal mucus. When administered to the colorectum in a hypotonic enema vehicle, we discovered that the osmotically-driven fluid absorption acts synergistically with the non-adhesive nature of MPP to draw MPP through mucus to uniformly coat the colorectal epithelium, including entering ulcerated tissue regions. Further, our pilot data suggests that MPP administered in mildly hypotonic vehicles provide improved treatment of severe acute inflammation compared to micronized drug enemas in a mouse model of UC. We propose to investigate enema vehicle composition and nanoparticle surface chemistry, drug loading, drug release kinetics, dose, and dosing schedule to test the hypothesis that drug delivery by MPP administered in optimized hypotonic vehicles leads to greatly improved efficacy in an animal model of UC.